The present invention provides for thiazolyl compounds useful as inhibitors of Tec family tyrosine kinases (especially inhibitors of Emt) and to pharmaceutical compositions containing such compounds. The present invention further provides for methods of using such compounds as immunosuppressive, anti-inflammatory, anti-allergic, and anti-cancer agents.
The present invention relates to inhibitors of the Tec family tyrosine kinases, and particularly, inhibitors of Emt. The Tec family kinases include Emt [expressed mainly in T cells; Gibson, S. et al., Blood 82, 1561-1572 (1993)], Txk [T-cell expressed kinase; Haire, R. N. et al., Hum. Mol. Genet. 3, 897-901 (1994)], Tec [tyrosine kinase expressed in hepatocellular carcinoma cells; Mano et al., Oncogene 5, 1781-1786 (1990)], Btk [Bruton""s tyrosine kinase; Vetrie, D. et al., Nature 361, 226-233, (1993)], and Bmx [bone marrow kinase, X-linked; Tamagnon, L. et al., Oncogene 9, 3683-3688 (1994)].
Mammalian immunity relies on the activation of T cells upon antigen presentation. The molecular mechanisms of T cell activation are initiated by the sequential activation of three distinct classes of non-receptor protein tyrosine kinases (PTK) following the engagement of the T cell antigen receptor (TCR). These three classes of PTK are the Src family kinases (Lck and Lyn), the Syk family kinases (ZAP-70 and Syk), and the Tec family kinases (Emt, Txk, and Tec). Inhibition of one or more of these kinases will impede the initiation signals and block T cell activation following antigen presentation. Thus, small molecular weight inhibitors of these kinases can be applied to treat the diseases that are associated with unwanted T cell activation.
Emt, also known as Itk (Interleukin-2-inducible T cell kinases) or Tsk (T-cell-specific tyrosine kinase), is expressed solely in T, natural killer, and mast cells. Emt is tyrosine-phosphorylated and activated in response to cross-linking of TCR, CD28, or CD2; and has been implicated in thymocyte development and the activation of T cells through TCR and CD28 engagement. Inside the cells, Emt is regulated by membrane recruitment followed by Lck phosphorylation and autophosphorylation. Emt is recruited to the membrane rafts for Lck phosphorylation through the interaction between the pleckstrin homology (PH) domain of Emt and the membrane lipid, phosphotidylinositol (3,4,5)-triphosphate [Bunnell et al., J. Biol. Chem. 275, 2219-2230 (2000)].
Gene knockout studies reveal that mice lacking Emt have decreased numbers of mature thymocytes, especially CD4+ T cells. The T cells isolated from such mice are compromised in their proliferative response to allogeneic MHC stimulation, and to anti-TCR/CD3 cross-linking [Liao X. C. and Littman, D. R., Immunity 3, 757-769 (1995)]. These T cells also exhibit defective PLCxcex31 tyrosine phosphorylation, inositol triphosphate production, Ca2+ moblization, and cytokine production (such as IL-2 and IFNxcex3) in response to TCR cross-linking [Schaeffer, E. M. et al., Science 284, 638-641 (1999)]. This genetic evidence indicates that Emt activity plays a requisite role in TCR signal transduction; and selective inhibition of Emt should have immunosuppressive, anti-inflammatory, and anti-proliferative effects. In addition, Emt-deficient mice are unable to establish functional Th2 cells (the IL-4 producing cells) and such mice are unable to clear parasitic infections depending upon a Th2 response [Fowell, D. J. et al., Immunity 11, 399-409 (1999)]. This observation also suggests that Emt may be an attractive target for modulating dysregulated allergic pathways mediated by Th2 cells.
The present invention provides thiazolyl compounds of the following formula I and salts thereof for use as Emt tyrosine kinase inhibitors: 
where
Q1 is thiazolyl;
Q2 is aryl or heteroaryl optionally independently substituted with one or more (preferably one to three) substituents R1a;
Z is
(1) xe2x80x94Oxe2x80x94,
(2) xe2x80x94Sxe2x80x94,
(3) xe2x80x94NR4xe2x80x94,
(4) xe2x80x94CR4R5xe2x80x94,
(5) xe2x80x94CR4R5xe2x80x94Oxe2x80x94CR4aR5a,
(6) xe2x80x94CR4R5xe2x80x94NR4bxe2x80x94CR4aR5axe2x80x94,
(7) xe2x80x94CR4R5xe2x80x94Sxe2x80x94CR4aR5axe2x80x94,
(8) xe2x80x94CR4R5xe2x80x94Oxe2x80x94,
(9) xe2x80x94Oxe2x80x94CR4R5xe2x80x94,
(10) xe2x80x94CR4R5xe2x80x94NR4bxe2x80x94,
(11) xe2x80x94NR4bxe2x80x94CR4R5xe2x80x94,
(12) xe2x80x94CR4R5xe2x80x94Sxe2x80x94,
(13) xe2x80x94Sxe2x80x94CR4R5xe2x80x94,
(14) xe2x80x94S(O)qxe2x80x94 where q is 1 or 2,
(15) xe2x80x94CR4R5xe2x80x94S(O)qxe2x80x94, or
(16) xe2x80x94S(O)qxe2x80x94CR4R5xe2x80x94;
R1 and R1a are independently
(1) hydrogen or R6,
(2) xe2x80x94OH or xe2x80x94OR6,
(3) xe2x80x94SH or xe2x80x94SR6,
(4) xe2x80x94C(O)qH, xe2x80x94C(O)qR6, or xe2x80x94Oxe2x80x94C(O)qR6,
(5) xe2x80x94SO3H or xe2x80x94S(O)qR6,
(6) halo,
(7) cyano,
(8) nitro,
(9) xe2x80x94Z4xe2x80x94NR7R8,
(10) xe2x80x94Z4xe2x80x94N(R9)xe2x80x94Z5xe2x80x94NR10R11,
(11) xe2x80x94Z4xe2x80x94N(R12)xe2x80x94Z5xe2x80x94R6, or
(12) xe2x80x94P(O)(OR6)2;
R2 and R3 are each independently H, xe2x80x94Z4xe2x80x94R6a, or xe2x80x94Z4xe2x80x94NR7aR8a 
R4, R4a, R4b, R5 and R5a are each independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, or heteroarylalkyl;
R6, R6a, R6b and R6c, are independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z1, Z2 and one or more (preferably, one or two) groups Z3,
R7, R7a, R8, R8a, R9, R10, R11 and R12 
(1) are each independently hydrogen, or xe2x80x94Z4R6b; or
(2) R7 and R8, or R7a and R8a may together be alkylene, alkenylene, or heteroalkylene, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and one or more groups Z3, or
(3) any two of R9, R10 and R11 may together be alkylene, alkenylene or heteroalkylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more Z1, Z2 and Z3;
Z1, Z2 and Z3 are each independently
(1) hydrogen or Z6,
(2) xe2x80x94OH or xe2x80x94OZ6,
(3) xe2x80x94SH or xe2x80x94SZ6,
(4) xe2x80x94C(O)qH, xe2x80x94C(O)qZ6, or xe2x80x94Oxe2x80x94C(O)qZ6,
(5) xe2x80x94SO3H, S(O)qZ6, or S(O)qN(Z9)Z6,
(6) halo,
(7) cyano,
(8) nitro,
(9) xe2x80x94Z4xe2x80x94NZ7Z8,
(10) xe2x80x94Z4xe2x80x94N(Z9)xe2x80x94Z5xe2x80x94NZ7Z8,
(11) xe2x80x94Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94Z6,
(12) xe2x80x94Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94H, (13) oxo,
(14) any two of Z1, Z2, and Z3 on a given substituent may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or
(15) any two of Z1, Z2, and Z3 on a given substituent may together be xe2x80x94Oxe2x80x94(CH2)qxe2x80x94Oxe2x80x94;
Z4 and Z5 are each independently
(1) a single bond,
(2) xe2x80x94Z11xe2x80x94S(O)qxe2x80x94Z12xe2x80x94,
(3) xe2x80x94Z11xe2x80x94C(O)xe2x80x94Z12xe2x80x94,
(4) xe2x80x94Z11xe2x80x94C(S)xe2x80x94Z12xe2x80x94,
(5) xe2x80x94Z11xe2x80x94Oxe2x80x94Z12xe2x80x94,
(6) xe2x80x94Z11xe2x80x94Sxe2x80x94Z12xe2x80x94,
(7) xe2x80x94Z11xe2x80x94Oxe2x80x94C(O)xe2x80x94Z12xe2x80x94,
(8) xe2x80x94Z11xe2x80x94C(O)xe2x80x94Oxe2x80x94Z12xe2x80x94; or
(9) alkyl
Z6 and Z6a are independently
(i) alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or
(iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the groups (2) to (15) of the definition of Z1;
Z7, Z8, Z9 and Z10 
(1) are each independently hydrogen or xe2x80x94Z4xe2x80x94Z6a;
(2) Z7 and Z8 may together be alkylene, alkenylene, or heteroalkylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more Z1, Z2 and Z3, or
(3) Z7 or Z8, together with Z9, may be alkylene, alkenylene, or heteroalkylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more Z1, Z2 and Z3;
Z11, and Z12 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene.
The following are definitions of terms used in this specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated.
The terms xe2x80x9calkxe2x80x9d or xe2x80x9calkylxe2x80x9d refer to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. The expression xe2x80x9clower alkylxe2x80x9d refers to alkyl groups of 1 to 4 carbon atoms.
The term xe2x80x9calkenylxe2x80x9d refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one double bond. Where an alkenyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a double bond.
The term xe2x80x9calkynylxe2x80x9d refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one triple bond. Where an alkynyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a triple bond.
The term xe2x80x9calkylenexe2x80x9d refers to a straight chain bridge of 1 to 5 carbon atoms connected by single bonds (e.g., xe2x80x94(CH2)xxe2x80x94 wherein x is 1 to 5), which may be substituted with 1 to 3 lower alkyl groups.
The term xe2x80x9calkenylenexe2x80x9d refers to a straight chain bridge of 2 to 5 carbon atoms having one or two double bonds that is connected by single bonds and may be substituted with 1 to 3 lower alkyl groups. Exemplary alkenylene groups are xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94C(CH3)2CHxe2x95x90CHxe2x80x94 and xe2x80x94CH(C2H5)xe2x80x94CHxe2x95x90CHxe2x80x94.
The term xe2x80x9calkynylenexe2x80x9d refers to a straight chain bridge of 2 to 5 carbon atoms that has a triple bond therein, is connected by single bonds, and may be substituted with 1 to 3 lower alkyl groups. Exemplary alkynylene groups are xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH(CH3)xe2x80x94Cxe2x89xa1Cxe2x80x94 and xe2x80x94Cxe2x89xa1Cxe2x80x94CH(C2H5)CH2xe2x80x94.
The term xe2x80x9cheteroalkylenexe2x80x9d refers to alkylene or alkenylene groups containing one or more heteroatoms N, O or S.
The terms xe2x80x9carxe2x80x9d or xe2x80x9carylxe2x80x9d refer to aromatic cyclic groups (for example 6 membered monocyclic, 10 membered bicyclic or 14 membered tricyclic ring systems) which contain 6 to 14 carbon atoms. Exemplary aryl groups include phenyl, naphthyl, biphenyl and anthracene.
The terms xe2x80x9ccycloalkylxe2x80x9d refers to saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 7 carbons, forming the ring and which may be fused to 1 or 2 aromatic or heterocyclo rings, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl, 
and the like.
The terms xe2x80x9chalogenxe2x80x9d and xe2x80x9chaloxe2x80x9d refer to fluorine, chlorine, bromine and iodine.
The terms xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheterocyclicxe2x80x9d or xe2x80x9cheterocycloxe2x80x9d refer to fully saturated or unsaturated, including aromatic (i.e. xe2x80x9cheteroarylxe2x80x9d) cyclic groups, for example, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, 5-tetrazolyl, 
and the like.
Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3 ,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl 
and the like.
Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
The term xe2x80x9cheteroarylxe2x80x9d refers to a 5- or 6-membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur, and such rings fused to an aryl, cycloalkyl, or heterocyclo ring (e.g. benzothiophenyl, indolyl), and includes possible N-oxides, such as 
and the like.
Where q is 1 or 2, xe2x80x9cxe2x80x94C(O)qHxe2x80x9d denotes xe2x80x94C(O)xe2x80x94H or xe2x80x94C(O)xe2x80x94OH; xe2x80x9cxe2x80x94C(O)qR6xe2x80x9d or xe2x80x9cxe2x80x94C(O)qZ6xe2x80x9d denote, respectively, xe2x80x94C(O)xe2x80x94R6 or xe2x80x94C(O)xe2x80x94OR6, or xe2x80x94C(O)xe2x80x94Z6 or xe2x80x94C(O)xe2x80x94OZ6; xe2x80x9cxe2x80x94Oxe2x80x94C(O)qR6xe2x80x9d or xe2x80x9cxe2x80x94Oxe2x80x94C(O)qZ6xe2x80x9d denote, respectively, xe2x80x94Oxe2x80x94C(O)xe2x80x94R6 or xe2x80x94Oxe2x80x94C(O)xe2x80x94OR6, or xe2x80x94Oxe2x80x94C(O)xe2x80x94Z6 or xe2x80x94Oxe2x80x94C(O)xe2x80x94OZ6; and xe2x80x9cxe2x80x94S(O)qR6xe2x80x9d or xe2x80x9cxe2x80x94S(O)qZ6xe2x80x9d denote, respectively, xe2x80x94SOxe2x80x94R6 or xe2x80x94SO2xe2x80x94R6, or xe2x80x94SOxe2x80x94Z6 or xe2x80x94SO2xe2x80x94Z6.
Compounds of the formula I may in some cases form salts which are also within the scope of this invention. Reference to a compound of the formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term xe2x80x9csalt(s)xe2x80x9d, as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. Zwitterions (internal or inner salts) are included within the term xe2x80x9csalt(s)xe2x80x9d as used herein (and may be formed, for example, where the R substituents comprise an acid moiety such as a carboxyl group). Also included herein are quaternary ammonium salts such as alkylammonium salts. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are useful, for example, in isolation or purification steps which may be employed during preparation. Salts of the compounds of the formula I may be formed, for example, by reacting a compound I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates, undecanoates, and the like.
Exemplary basic salts (formed, for example, where the R substituents comprise an acidic moiety such as a carboxyl group) include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines, N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. The basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term xe2x80x9cprodrugxe2x80x9d, as employed herein, denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula I, or a salt and/or solvate thereof. Solvates of the compounds of formula I are preferably hydrates.
All stereoisomers of the present compounds, such as those which may exist due to asymmetric carbons on the R substituents of the compound of the formula I, including enantiomeric and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
Throughout the specification, groups and substituents thereof are chosen to provide stable moieties and compounds.
Preferred compounds within the scope of the formula I include those wherein:
Q2 is phenyl optionally substituted with one or more groups as defined in R1a (especially, alkyl, hydroxy, alkoxy, haloalkoxy, halo, nitro, xe2x80x94C(O)qR6, xe2x80x94C(O)qH, xe2x80x94Z4xe2x80x94NR7R8, xe2x80x94Z4xe2x80x94N(R12)xe2x80x94Z5xe2x80x94Z6, or xe2x80x94Z4xe2x80x94N(R9)xe2x80x94Z5xe2x80x94NR10R11);
Z is selected from xe2x80x94Sxe2x80x94, xe2x80x94CR4R5xe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94CR4R5xe2x80x94, CR4R5xe2x80x94Oxe2x80x94CR4aR5axe2x80x94, xe2x80x94CR4R5xe2x80x94NR4xe2x80x94CR4aR5axe2x80x94, xe2x80x94CR4R5xe2x80x94, xe2x80x94CR4R5xe2x80x94SO2xe2x80x94 or xe2x80x94CR4R5xe2x80x94S(O)xe2x80x94;
R1 is hydrogen;
R2 is hydrogen or alkyl; and
R3 is H, xe2x80x94Z4R6a or xe2x80x94Z4NR7aR8a.
More preferred compounds within the scope of formula I include those wherein:
Q2 is phenyl optionally substituted with one or more groups selected from alkyl, alkoxy, hydroxy, xe2x80x94C(O)R6 (especially wherein R6 is optionally substituted alkyl or heterocyclo (especially piperazinyl), xe2x80x94C(O)NR7R8 or xe2x80x94NR7R8;
Z is selected from xe2x80x94CR4R5xe2x80x94Oxe2x80x94CR4aR5axe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CR4R5xe2x80x94Sxe2x80x94 or xe2x80x94Sxe2x80x94CR4R5xe2x80x94;
R1 is hydrogen;
R2 is hydrogen or alkyl; and
R3 is xe2x80x94Z4R6a, especially where:
(a) Z4 is a single bond and R6a is optionally substituted heteroaryl (preferably pyridinyl, pyrimidinyl, or quinolinyl optionally substituted with one or more Z1, Z2 or Z3 which are preferably alkyl, hydroxyalkyl, halo, xe2x80x94Z4xe2x80x94NZ7Z8, xe2x80x94C(O)qH, xe2x80x94C(O)qZ6, xe2x80x94OZ6 or heterocyclo)
(b) Z4 is xe2x80x94C(O)xe2x80x94 and R6a is
(1) aryl (especially phenyl) optionally substituted with one or more Z1, Z2 or Z3 (preferably xe2x80x94Z4xe2x80x94NZ7Z8, xe2x80x94OZ6Za, hydroxy, heterocyclo, or alkyl which may be optionally substituted with any of the preceding preferred Z1, Z2 or Z3 groups) (where present, at least one substituent is preferably in the para position);
(2) alkyl optionally substituted with one or more Z1, Z2 or Z3;
(3) cycloalkyl (especially cyclopropyl) optionally substituted with one or more Z1, Z2 or Z3 (especially aryl, aralkyl, halo, hydroxy, xe2x80x94C(O)qH, xe2x80x94C(O)qZ6 or alkyl optionally substituted with hydroxy, xe2x80x94OZ6 or xe2x80x94Z4xe2x80x94NZ7Z8)); or
(4) heterocyclo (especially pyrrolidinyl, piperidyl, piperidenyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl or pyrimidinyl) optionally substituted with one or more Z1, Z2 or Z3 (especially xe2x80x94Z4xe2x80x94NZ7Z8, xe2x80x94C(O)qH, xe2x80x94C(O)qZ6, or alkyl optionally substituted with hydroxy, xe2x80x94OZ6 or xe2x80x94Z4xe2x80x94NZ7Z8); or
(c) Z4 is xe2x80x94C(O)xe2x80x94Oxe2x80x94 and R6a is alkyl, cycloalkyl, aryl or aralkyl, any of which may be optionally substituted with one or more Z1, Z2 or Z3.
Preferred compounds within the scope of formula I include compounds of the following formula II: 
where Z, Q2, R1, R2 and R3 are as described above (including the description of preferred substituents). Additionally, preferred compounds within the scope of formula II include compounds of the following formulae IIIa, IIIb and IIIc: 
where
Z is as described above (preferably xe2x80x94Sxe2x80x94, xe2x80x94CR4R5xe2x80x94Sxe2x80x94, or xe2x80x94Sxe2x80x94CR4R5xe2x80x94 where R4 and R5 are H);
R1 is as described above (preferably H);
R2 and R3 are as described above (including the description of preferred substituents);
R1aa is xe2x80x94C(O)qH, xe2x80x94C(O)qR6, xe2x80x94Z4xe2x80x94NR7R8, xe2x80x94Z4xe2x80x94N(R9)xe2x80x94Z5xe2x80x94NR10R11 or xe2x80x94Z4xe2x80x94N(R9)xe2x80x94Z5xe2x80x94R6; and
R1ab, R1ac and R1ad are independently selected from any R1 group (especially, H, alkyl, hydroxy, nitro, halo, xe2x80x94OR6, xe2x80x94NR7R8, xe2x80x94C(O)qH or xe2x80x94C(O)qR6).
Preferred compounds within the scope of formulae III include compounds of the following formula IV 
where
Z, R1, R1aa, R2, and R3 are as described above; and
One of R1ab, R1ac and R1ad is H and the other two are independently alkyl, alkoxy, haloalkoxy, hydroxy, nitro, halo, xe2x80x94NR7R8, xe2x80x94C(O)qH or xe2x80x94C(O)qR6) (preferably alkyl or alkoxy). (preferably, R1c is H when Z is xe2x80x94Sxe2x80x94, and R1d is H when Z is xe2x80x94Sxe2x80x94CR4R5xe2x80x94 or xe2x80x94Oxe2x80x94CR4R5xe2x80x94);
Compounds within the scope of formula IV include compounds of the following formula V: 
where
Z, R1, R1ab, R1ac, R1ad, R2 and R3 are described for formula IV;
X1 is C or N (preferably N);
X2 is CZ3a, NZ3a, O or S (preferably CZ3a, NZ3a or O) (more preferably NZ3a);
Z1 and Z2 are as described for formula I (preferably H);
Z3a is H, hydroxy, optionally substituted alkyl (especially optionally substituted with hydroxy, cyano, aryl, xe2x80x94OZ6, xe2x80x94Z4xe2x80x94NZ7Z8, xe2x80x94C(O)qH or xe2x80x94C(O)qZ6), optionally substituted heterocyclo (preferably optionally substituted piperidinyl, tetrazolyl, pyridinyl, pyrimidinyl, or pyrrazolyl), optionally substituted aryl or aralkyl (especially optionally substituted with halo), xe2x80x94OZ6, C(O)qH, C(O)qZ6a, xe2x80x94Z4xe2x80x94NZ7Z8 (especially where Z4 is a bond or xe2x80x94C(O)xe2x80x94), or xe2x80x94Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94Z6 (especially where Z4 is a bond or xe2x80x94C(O)xe2x80x94 and Z5 is xe2x80x94Oxe2x80x94, xe2x80x94SO2xe2x80x94, or xe2x80x94C(O)Oxe2x80x94);
n is 1 to 3; and
m is zero to 2.
The compounds of the formula I may be prepared by methods such as those illustrated in the following Schemes A through C and I through VIII. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. All documents cited are incorporated herein by reference in their entirety. Starting materials are commercially available or readily prepared by one of ordinary skill in the art. Constituents of compounds are as defined elsewhere in the specification or as specifically defined in a scheme.
The methods described herein may be carried out with starting materials and/or reagents in solution or alternatively, where appropriate, with one or more starting materials or reagents bound to a solid support (see (1) Thompson, L. A., Ellman, J. A., Chemical Reviews, 96, 555-600 (1996); (2) Terrett, N. K., Gardner, M., Gordon, D. W., Kobylecki, R. J., Steele, J., Tetrahedron, 51, 8135-8173 (1995); (3) Gallop, M. A., Barrett, R. W., Dower, W. J., Fodor, S. P. A., Gordon, E. M., Journal of Medicinal Chemistry, 37, 1233-1251 (1994); (4) Gordon, E. M., Barrett, R. W., Dower, W. J., Fodor, S. P. A., Gallop, M. A., Journal of Medicinal Chemistry, 37, 1385-1401 (1994); (5) Balkenhohl, F., von dem Bussche-Hxc3xcnnefeld, Lansky, A., Zechel, C., Angewandte Chemie International Edition in English, 35, 2288-2337 (1996); (6) Balkenhohl, F., von dem Bussche-Hxc3xcnnefeld, Lansky, A., Zechel, C., Angewandte Chemie, 108, 2436-2487 (1996); and (7) Sofia, M. J., Drugs Discovery Today, 1, 27-34 (1996)).
Compounds of formula I that contain chiral centers maybe obtained in non-racemic form by non-racemic synthesis or resolution by methods well known to those skilled in the art. Compounds that are non-racemic are designated as xe2x80x9cchiralxe2x80x9d in the examples.
In the examples described below it may be necessary to protect reactive functionality such as hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in reactions. The introduction and removal of protecting groups are well known to those skilled in the art, for example see (Green, T. W. in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, 1991). 
Scheme A illustrates a general method for forming compound Ia which is a compound of formula I where Zxe2x95x90O, S, or NR4. Compound Ia can be formed by reacting compound i with compound ii in the presence of an organic or inorganic base e.g. alkalimetal alkoxide, alkyl or aryl lithium, or Grignard reagent in a protic or aprotic solvent e.g. tetrahydrofuran, ether, methyl alcohol, ethanol or dimethyl formamide at a temperature of 78xc2x0 C. to 100xc2x0 C. 
Scheme B illustrates a general method for forming compound Ia which is a compound of formula I where Z=O, S, NR4. Compound Ia can be formed by reacting compound iii with compound iv in presence of an organic or inorganic base e.g. alkali metal alkoxide, alkalimetal hydride, alkyl or aryl lithium or Grignard reagent in a protic or a protic solvent e.g. THF, ether, methanol, ethanol or DMF at a temperature of xe2x88x9278xc2x0 C. to 100xc2x0 C. 
Scheme C illustrates a general method for forming Compound Ib which is a compound of formula I where Zxe2x95x90CR4R5. Compound Ib can be formed by reacting Compound v with an organometallic reagent e.g. alkyl or aryl lithium or cuprate or Grignard reagent and then reacting with Compound vi in an aprotic solvent e.g. ether, THF, DMF at a temperature of xe2x88x9278xc2x0 C. to 60xc2x0 C.
Methods for preparing preferred examples of compound I are illustrated in Schemes I to IX. 
As shown in Scheme I, amine Ic which can be formed by methods described in Schemes A, B or C can be reacted with a chloroformate 1 or dicarbonate 2 to form Id. Compound Id can be treated with a base such as sodium hydride, sodium/potassium hexamethyl disilazide, or lithium diisopropylamide (LDA), and an alkylating agent R2X where X is halogen and R2 is preferably alkyl, arylalkyl or cycloalkylalkyl to form Compound Ie. 
Scheme II illustrates methods which may be used for the preparation of Compounds Ig, Ih, Ii, Ij and Ik which are compounds of formula I where R2 is any group as defined, R3 is an acyl or thioacyl, Z is not xe2x80x94NH and R1 is not a primary or secondary amine. Ig, Ih, Ii, Ij and Ik have other particular substituents which are specified in this Scheme and below. The starting compound If can be prepared by suitable methods described in Schemes A, B or C.
Amide Ig can be prepared by treatment of amine If with a carboxylic acid 3 in the presence of reagents which activate the carboxyl group for reaction as described above, for example BOP reagent, HATU and carbodiimides such as DCC or EDCI either alone or in combination with a hydroxybenzotriazole. Alternatively, the alidhalide 4 may be reacted with amine compound If in presence of an acid scavenger such as pyridine ordiisopropyl ethyl amine. The corresponding thioamide Ih can be prepared by treatment of amide Ig with Lawesson""s reagent as described above. Carbamate Ii can be prepared by treatment of amine compound If with a chloroformate 1 or dicarbonate 2 in the presence of an acid scavenger such as diisopropylethylamine, triethylamine or an aqueous inorganic base such as sodium/potassium bicarbonate, sodium/potassium carbonate or hydroxide.
The urea Ij may be prepared by treatment of amine compound If with either: 1) a chloroformate 1, such as phenyl chloroformate, followed by reaction with an amine 5; 2) a carbamoyl chloride 6 in presence of an acid scavenger such as diisopropylethylamine; or 3) reaction with an isocyanate 7a (where Rc in Ii=H). The corresponding thiourea Ik may be prepared by treatment of amine compound Ie with a isothiocyanate 7b.
Ra is selected from those groups included in the definition of R6a such that the group xe2x80x94C(xe2x95x90A)xe2x80x94Ra is an acyl group within the definition of R3. Rb and Rc are selected from those groups included in the definitions of R7a and R8a, such that the group xe2x80x94C(xe2x95x90A)xe2x80x94N(Rb)(Rc) is an acyl or thioacyl group within the definition of R3. 
Scheme III illustrates a method which can be used for the preparation of Il, which is a compound of formula I where R2 is any group as defined other than acyl, and which is selected such that the nitrogen to which it is attached is basic, R3 is alkyl, cycloalkyl, cycloalkyl-alkyl, cycloalkenylalkyl, aralkyl or saturated heterocycle and Z is not xe2x80x94NH. The starting compounds Ik and Ic can be prepared by suitable methods described in Schemes A, B and C. As shown in Scheme III, amine compound Ik is reacted with an aldehyde or ketone 8 under reductive amination conditions described above to give the Compound Il. Compound Il may also be prepared by treatment of an amine compound Ic, where R2 and R3 are hydrogen, with t-butyl/t-amyl nitrite or sodium nitrite and an acid such as HCl, H2SO4 in presence of a copper (II) halide to give the halo compound vii, followed by displacement with amine 9 in the presence or absence of a base such as sodium or potassium hydride or the like (see Lee et al., J. Heterocyclic Chemistry 22,1621,1985). Rd and Re are independently selected from hydrogen, alkyl, aryl, cycloalkyl or cycloalkenyl or together are alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring, such that the group xe2x80x94CH(Rd)(Re) is a group within the definition of R. 
As shown in Scheme IV, when R2 is any group as defined other than acyl, and is selected such that the nitrogen to which it is attached is basic, R3 is an aryl or heteroaryl, amine compound Ik may be reacted with a halophenyl or haloheteroaromatic group 10 in the presence of a Pd(O)catalyst (See J. Am. Chem. Soc. 118, 7215, 1996) to give amine Il, which is a compound of formula I having the particular substituents described in this Scheme. The starting compound II can be prepared by suitable methods described in Scheme A, B or C. 
As shown in Scheme V, when R2 is any group as defined, R3 is a heteroaromatic group, amine compound, Im may be reacted, in the presence of a base if needed, with a 2-halo-substituted heteroaromatic compound 11 where Qa, together with atoms to which it is bonded, forms a 5- or 6-membered monocyclic or 10- to 12-membered bicyclic heteroaromatic group (such as forming 2-chloropyridine, 2-chloropyrimidine or 2-chloroquinoline) to give the amine compound In, where In is a compound of formula I having the particular substituents described in this scheme. The starting compound Im can be prepared by suitable methods described in Schemes A, B and C. 
As shown in Scheme VI, thiourea compound Io may be reacted with the appropriate amine 12 in the presence of bis-(2-oxo-3-oxazolidinyl) phosphinic chloride (BOP chloride), benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluoro-phosphate (BOP-reagent), [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium]hexafluorophosphate (HATU) and a carbodiimide such as dicyclohexylcarbodiimide (DCC) or 3-ethyl-e(dimethylamino) propyl carbodiimide (EDCI) or diisopropylcarbodiimide (DIC) in the presence of an organic base such as triethylamine, diisopropylethylamine or dimethylaminopyridine in solvents such as dimethylformamide, dichloromethane or tetrahydrofuran to form compound Ip, which is a compound of formula I having the particular substituents described in this scheme.
Alternatively, compound Io can be reacted with the appropriate amine 12 in the presence of a mercury (II) salt such as mercury chloride, or by other known methods in the literature, to form Ip.The starting material Io can be prepared by suitable methods described in Schemes A, B, or C or Scheme II. 
As shown in Scheme VII, amine Iq can be reacted with diphenyl cyanocarbonimidate 13 either alone or in the presence of a base such as sodium hydride, sodium/potassium hexamethyldisilazide or dimethylaminopyridine in acetonitrile, tetrahydrofuran or dimethylformamide at room temperature or elevated temperature to form intermediate compound Ir which can be reacted with amine 14 to form compound Is, which is a compound of formula I having the particular substituents described in this scheme. The starting material Iq can be prepared by suitable methods described in Schemes A, B or C. 
As shown in Scheme VIII, compound Iq can be reacted with either 15 or 16 either alone or in the presence of a base such as sodium hydride, sodium/potassium hexamethyldisilazide or dimethylaminopyridine in dimethylformamide or tetrahydrofuran at room temperature or elevated temperature to form compounds It or Iu, respectively, which can be reacted separately with amine 14 at room temperature or elevated temperature to form compound Iv or Iw, respectively. Compounds Iv and Iw are compounds of formula I having the particular substituents as described in this scheme. The starting material Iq can be prepared by suitable methods described in Schemes A, B or C. 
As shown in Scheme IX, compound Ix may be reduced using, for example, lithium aluminum hydride in tetrahydrofuran at a temperature of 0-55xc2x0 C., or reacted with alkyl or aryl metal derivatives, such as alkyl lithium or Grignard reagents, in aprotic solvents such as diethyl ether or tetrahydrofuran, at a temperature of xe2x88x9278 to 100xc2x0 C. to afford alcohol Iy. Alcohol Iy may then be reacted with compound vi alone or in the presence of organic or inorganic bases, such as sodium hydride, lithium hexamethyldisilazide, or potassium t-butoxide and the like, in a solvent such as dimethylformamide, and at a temperature of 0-100xc2x0 C. to give compound Iaa. Alternatively, the alcohol moiety of Iy may be transformed into a leaving group via tosylation or conversion to a halide and then reacted with compound 18 alone or in the presence of bases such as sodium hydride in solvents such as tetrahydrofuran or dimethylformamide at a temperature from 0-100xc2x0 C. to give compound Ibb.
The compounds of the present invention are immunosuppressive, anti-inflammatory, anti-allergic, and anti-cancer agents. The compounds of the present invention inhibit Tec family tyrosine kinases (especially Emt) and are thus useful in the treatment, including prevention and therapy, of Tec family tyrosine kinase-associated disorders, especially Emt-associated disorders. xe2x80x9cTec family tyrosine kinase-associated disordersxe2x80x9d are those disorders which result from aberrant Tec family tyrosine kinase activity, and/or which are alleviated by the inhibition of one or more of these enzymes. Compounds within the scope of the present invention selectively inhibit Emt and are thus useful in the treatment, including prevention and therapy, of a range of disorders associated with the activation of Emt (e.g., inflammatory disorders, allergic disorders and cancer). In addition to Emt, the compounds of the present invention inhibit other Tec family kinases including Btk, Txk, Tec, and Bmx and are useful in the treatment of the disorders associated with the activation of these Tec family kinases. Such disorders are exemplified by, but are not limited to, transplant rejection; transplantation tolerance induction; arthritis including rheumatoid arthritis, psoriatic arthritis, and osteoarthritis; multiple sclerosis; chronic obstructive pulmonary disease (COPD) such as emphysema; inflammatory bowel diseases including ulcerative colitis and Crohn""s disease; lupus (systemic lupus erythematosis); graft vs. host disease; T-cell mediated hypersensitivity diseases including contact hypersensitivity, delayed-type hypersensitivity, and gluten-sensitive enteropathy (Celiac disease); psoriasis; contact dermatitis (including that due to poison ivy); Hashimoto""s thyroiditis; Sjogren""s syndrom; autoimmune hyperthyroidism such as Graves""s disease; Addison""s disease (autoimmune disease of the adrenal glands); autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome); autoimmune alopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism; Guillain-Barre syndrome; diabetes (both type I and type II); other autoimmune diseases; cancers such as leukemias and lymphomas; glomerulonephritis; serum sickness; uticaria; allergic diseases including respiratory allergies (asthma, hayfever, allergic rhinitis) and skin allergies; scleracierma; mycosis fungoides; acute inflammatory responses (such as acute respiratory distress syndrome and ischemia/reperfusion injury); dermatomyositis; alopecia areata; chronic actinic dermatitis; eczema; Behcet""s disease; Pustulosis palmoplanteris; Pyoderma gangrenum; Sezary""s syndrom; atopic dermatitis; systemic schlerosis; and morphea.
In a particular embodiment, the compounds of the present invention are useful for the treatment of the aforementioned exemplary disorders irrespective of their etiology, for example, for the treatment of transplant rejection, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease, inflammatory bowel disease, lupus, graft vs. host disease, T-cell mediated hypersensitivity disease, psoriasis, Hashimoto""s thyroiditis, Guillain-Barre syndrom, cancer, contact dermatitis, allergic disease such as allergic rhinitis, asthma, ischemic or reperfusion injury, or atopic dermatitis whether or not associated with the Tec family tyrosine kinases.
The present invention also provides pharmaceutical compositions comprising at least one of the compounds of the formula I capable of treating a protein tyrosine kinase-associated disorder in an amount effective therefor, and a pharmaceutically acceptable vehicle or diluent. The compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
The compounds of the formula I may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrastemal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds may also be administered liposomally.
Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The present compounds may also be delivered through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used. Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations may also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g., Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer""s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
Exemplary compositions for rectal administration include suppositories which may contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene glycol).
The effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for an adult human of from about 0.1 to 100 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats and the like, subject to protein tyrosine kinase-associated disorders.
The compounds of the present invention may be employed alone or in combination with each other and/or other suitable therapeutic agents useful in the treatment of Tec family tyrosine kinase-associated disorders such as Emt inhibitors other than those of the present invention, antiinflammatories, antiproliferatives, chemotherapeutic agents, immunosuppressants, anticancer agents and cytotoxic agents.
Exemplary such other therapeutic agents include the following: protein tyrosine kinase inhibitors (such as those disclosed in WO 00/62778), cyclosporins (e.g., cyclosporin A), CTLA4-Ig, LEA-29Y, antibodies such as anti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibody OKT3, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 (i.e., CD154), fusion proteins constructed from CD40 and gp39 (CD40Ig and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NF-kappa B function, such as deoxyspergualin (DSG), non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, steroids such as prednisone or dexamethasone, gold compounds, antiproliferative agents such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such as azathiprine and cyclophosphamide, phosphodiesterase (PDE) inhibitors, antihistamines, p38 MAPK inhibitors, LTD4 inhibitors such as zafirlukast (ACCOLATE) and montelukast (SINGULAIR), TNF-xcex1 inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor such as etanercept (Enbrel), rapamycin (sirolimus or Rapamune), leflunimide (Arava), and cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex) and rofecoxib (Vioxx), or derivatives thereof, and the PTK inhibitors disclosed in the following U.S. Patent Applications, incorporated herein by reference in their entirety: Serial No. 60/056,770, filed Aug. 25, 1997 Serial No. 60/069,159, filed Dec. 9, 1997, Ser. No. 09/097,338, filed Jun. 15, 1998, Serial No. 60/056,797, filed Aug. 25, 1997, Ser. No. 09/094,797, filed Jun. 15, 1998, Serial No. 60/065,042, filed Nov. 10, 1997, Ser. No. 09/173,413, filed Oct. 15, 1998, Serial No. 60,076,789, filed Mar. 4, 1998, and Ser. No. 09,262,525, filed Mar. 4, 1999. See the following documents and references cited therein: Hollenbaugh, D., Douthwright, J., McDonald, V., and Aruffo, A., xe2x80x9cCleavable CD40Ig fusion proteins and the binding to sgp39xe2x80x9d, J. Immunol. Methods (Netherlands), 188(1), p. 1-7 (Dec. 15, 1995); Hollenbaugh, D., Grosmaire, L. S., Kullas, C. D., Chalupny, N. J., Braesch-Andersen, S., Noelle, R. J., Stamenkovic, I., Ledbetter, J. A., and Aruffo, A., xe2x80x9cThe human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activityxe2x80x9d, EMBO J (England), 11(12), p 4313-4321 (December 1992); and Moreland, L. W. et al., xe2x80x9cTreatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein, New England J. of Medicine, 337(3), p. 141-147 (1997).
Exemplary classes of anti-cancer agents and cytotoxic agents include, but are not limited to: alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes; antimetabolites, such as folate antagonists, purine analogues, and pyrimidine analogues; antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such as L-asparaginase; famesyl-protein transferase inhibitors; hormonal agents, such as glucocorticoids, estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone anatagonists, octreotide acetate; microtubule-disruptor agents, such as ecteinascidins or their analogs and derivatives; microtubule-stabilizing agents such as paclitaxel (Taxol(copyright)), docetaxel (Taxotere(copyright)), and epothilones A-F or their analogs or derivatives; plant-derived products, such as vinca alkaloids, epipodophyllotoxins, taxanes; and topoisomerase inhibitors; prenyl-protein transferase inhibitors; and miscellaneous agents such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, platinum coordination complexes such as cisplatin and carboplatin; and other agents used as anti-cancer and cytotoxic agents such as biological response modifiers, growth factors; immune modulators, and monoclonal antibodies. The compounds of the invention may also be used in conjunction with radiation therapy.
Representative examples of these classes of anti-cancer and cytotoxic agents include, but are not limited to, mechlorethamine hydrochloride, cyclophosphamide, chlorambucil, melphalan, ifosfamide, busulfan, carmustin, lomustine, semustine, streptozocin, thiotepa, dacarbazine, methotrexate, thioguanine, mercaptopurine, fludarabine, pentastatin, cladribin, cytarabine, fluorouracil, doxorubicin hydrochloride, daunorubicin, idarubicin, bleomycin sulfate, mitomycin C, actinomycin D, safracins, saframycins, quinocarcins, discodermolides, vincristine, vinblastine, vinorelbine tartrate, etoposide, teniposide, paclitaxel, tamoxifen, estramustine, estramustine phosphate sodium, flutamide, buserelin, leuprolide, pteridines, diyneses, levamisole, aflacon, interferon, interleukins, aldesleukin, filgrastim, sargramostim, rituximab, BCG, tretinoin, irinotecan hydrochloride, betamethosone, gemcitabine hydrochloride, altretamine, and topoteca and any analogs or derivatives thereof.
Preferred members of these classes include, but are not limited to paclitaxel, cisplatin, carboplatin, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C, ecteinascidin 743, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, and leurosine.
Examples of anti-cancer and other cytotoxic agents include the following: epothilone derivatives as found in U.S. Ser. No. 09/506,481 filed Feb. 17, 2000; German Patent No. 4138042.8; WO 97/19086, WO 98/22461, WO 98/25929, WO 98/38192, WO 99/01124, WO 99/02224, WO 99/02514, WO 99/03848, WO 99/07692, WO 99/27890, WO 99/28324, WO 99/43653, WO 99/54330, WO 99/54318, WO 99/54319, WO 99/65913, WO 99/67252, WO 99/67253, and WO 00/00485; cyclin dependent kinase inhibitors as found in WO 99/24416; and prenyl-protein transferase inhibitors as found in WO 97/30992 and WO 98/54966.
The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians"" Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
Compounds within the scope of the present invention can be assayed for Tec family tyrosine kinase inhibitory activity using methods such as those described by Hawkins, J. and Marcy, A. Prot. Express. Purif 2001, 22, 211-219, employing modifications readily known to those of skill in the art.
The following example compounds are Tec family tyrosine kinase inhibitors (especially Emt inhibitors) and illustrate embodiments of the present invention. These examples are not intended to limit the scope of the claims. Compounds of the Examples are identified by the example and step in which they are prepared (for example, xe2x80x9c1Axe2x80x9d denotes the title compound of step A of Example 1), or by the example only where the compound is the title compound of the example (for example, xe2x80x9c2xe2x80x9d denotes the title compound of Example 2).